Chronic infection with hepatitis B virus (HBV) is the major risk factor for primary hepatocellular carcinoma, accounting for 80% of the cases worldwide. Forty percent of male chronic HBV carriers will eventually die of PHC and another 15% are projected to die of cirrhosis. This risk is unevenly distributed, but little is known about which virus related factors are associated with risk of PHC. In Project I, Prevention of Primary Liver Cancer, a cohort of 5,000 chronic carriers is being recruited from the East Asian immigrant and refugee population of the Delaware Valley. The objective of Project I is to detect PHCs at an early treatable stage using alpha fetoprotein monitoring. The objective of Project II is to test the hypothesis that persistent replication of HBV is associated with an increased risk of developing chronic Liver disease and PHC. This hypothesis will be tested by assaying separately collected serum samples for HBV markers known to be associated with replication HBsAg and HBV DNA, and a number of recently identified markers which may be directly or inversely associated with replication. These include HB Pre- S1, HB Pre-S2, anti-pol (anti-DNA polymerase), anti-Pre-S1, anti-Pre-S2, HBxAg and anti-HBx. Data collected in Project I including age, sex, clinical, biochemical, and behavioral information will be used as covariates in this project. Factors will be analyzed for their relation to each other, to HBV replication, to chronic liver disease, and their risk of PHC. Univariate and multivariate analyses will be used to identify individual and combination of factors which impact the highest risk. Identification of virus associated risk factors may permit a deeper understanding of the pathogenesis of chronic liver disease and PHC. Identification of individuals at highest risk would identify those persons who would benefit most from therapeutic and preventative intervention strategies. Ideally, knowledge of viral risk factors could lead to the development of methods for preventing serious liver disease from ever occurring.